Atherosclerotic vascular disease in the form of coronary artery and peripheral vascular disease is the largest cause of mortality in both the United States and Europe. Surgical mainstays of therapy for affected vessels include bypass grafting with autologous veins or arteries; however, adequate autologous vein is lacking in many patients. Prosthetic vascular grafts are therefore required.
Several materials are presently available for use as prosthetic vascular grafts and other surgical prostheses. These include polytetrafluoroethylene (PTFE) and Dacron. These two materials are rigid and when used as grafts create a compliance mismatch at the anastomosis. The primary patency rates of PTFE or Dacron grafts is 20 to 30% at 4 to 5 years. A further material which can be used as a vascular graft is polyurethane (PU). This material has the advantage that it is more elastic and therefore more similar to the blood vessel which it is to mimic. PU grafts are thus compliant grafts in the sense that they behave in a similar way to a natural blood vessel in the body. In particular, they flex more readily than PTFE or Dacron grafts when the site at which they are contained flexes.
Compliance is regarded by many as the key attribute required for matching cardiovascular prostheses to the arterial tree. The development of a compliant material is therefore thought to be an important step towards the improvement of clinical performance of small diameter grafts, particularly in low flow situations such as below knee arterial bypass. Obtaining long term compliance has been an elusive goal as currently used grafts rely on an overall external dilation to provide compliance. However, perivascular ingrowth prevents external dilation and thus compliance is lost after a relatively short period of time.
PU based grafts however achieve compliance via a different mechanism. Increases in volume are accommodated by a mechanism of wall compression without the need for external dilation. The use of compliant PU rather than a more rigid material has previously been found to increase the patency rate of the graft (Seifalian et al, Tissue Engineering of Vascular Prosthetic Grafts, 1999 R. G. Landes).
However, the use of any of these materials alone for the graft is problematic: as the blood flows through the graft, particles such as platelets tend to adhere to the surface of the graft or the blood may coagulate, in particular in the area of the anastomoses, in particular the distal anastomosis, but also along the luminal surface of the graft. This causes a narrowing (stenosis) in the inner diameter of the vessel, which is particularly problematic in the context of grafts of low diameter (for example 5 mm or less) where there is little blood flow. The major area which is affected is the distal anastomosis, where the downstream end of the graft-meets the blood vessel. This has mainly been attributed to the lack of coverage by endothelial cells, the natural lining of normal blood vessels. The endothelium has the potential to release anticoagulant and platelet active substances which facilitate normal blood flow.
In order to address this problem, seeding grafts with endothelial cells, both before and during surgery, has been attempted. Broadly, seeding is carried out by extracting endothelial cells from the patient's adipose tissue or a vein and using these cells to coat the inside of the graft, in order to mimic the natural endothelium. Although seeding the graft in this manner has been shown to increase the patency rate, seeded cells adhere very poorly to the graft surface, in particular to PTFE. Indeed, where cells are seeded directly onto the graft lumen, only 1 to 14% of cells remain attached following exposure to blood flow.
Of crucial importance therefore in endothelial seeding is the ability of the seeded cells to resist the shear stress caused by the flow of blood through the vessel. The pulsatile nature of the blood flow makes it particularly likely that the cells will be swept away if not firmly attached to the surface of the graft. Where endothelial seeding is more difficult, e.g. with PTFE, the effect of shear stress is vital, although it is very important when using any graft material.
Numerous techniques have been developed to aid attachment of endothelial cells to the polymer surface. For example, fibronectin glue enriched with RGD (Arg-Gly Asp) has been used to increase adherence of endothelial cells. Various alternative bonding chemistries have also be attempted to attach to the surface of the polymer moieties such as RGD and heparin that aid endothelium formation, as well as other anticoagulants. However, recent in vitro studies have shown that these bonding chemistries lead to alterations in the mechanical properties of the polymer. In vivo studies have also shown that the presence of the anticoagulants on the polymer surface can lead to alterations in the chemical behaviour of the polymer, resulting in aneurismal failure.
For surgical use, the acceptable scope for variation in the physical and chemical properties of the graft is small. The change brought about by bonding anticoagulants and other materials to the surface of the polymer may be sufficient to cause failure of the graft in vivo. A new approach is therefore required, by which biocompatibility of the polymer is improved without the need for such bonding steps.
A further problem associated with PUs is the possibility of degradation in vivo over long periods of time. Clinically, polyurethanes used for permanent implants have a very mixed record due to the variety of degradation mechanisms that come into play, especially in the case of their usage for vascular grafts for lower limb bypass. In such lower limb bypass grafts, the site of degradation has invariably been the amorphous or soft segment, typically an ester, ether or carbonate.
Degradation is a particular problem for materials having heparin attachments. Heparin tends to attract moisture, which in turn attracts biological enzymes. These enzymes cause the polymer to degrade, thus leading to an unacceptably short lifetime for the heparin-bound polymer.
The resistance of hydrolysable polymer structures to hydrolysis can be improved by incorporation of hydrocarbons such as silicones, sulfones, halocarbons and/or isolated carbonyl-containing molecules (ketones) in the polymer structure. Recent work has produced a number of polyurethanes in which siloxane blocks have been incorporated into polyurethanes. However, these structures have been found to have poor mechanical properties, possibly due to the presence of crystalline areas in the polymer. The poor resistance of these types of polymer to tear, and their tendency to discolour, have been noted as particular problems.
Previously known siloxane polymers also have inferior biological properties, noted by their reduced ability to support the growth of endothelial cells used in seeding bypass grafts. An alternative polymer is therefore required which addresses these difficulties by providing improved mechanical properties, as well as improved biological properties, including compatibility to blood and the ability to support endothelial cell growth.